es up to 200, 180 and 100 mg/kg, respectively. oral absorption in the rat amounts to approximately 90% of the administered dose. because animal reproduction studies are not always predictive of human response, this drug should be used only if clearly indicated during the first trimester of pregnancy.

ndida albicans . strains of fungi having a natural resistance to clotrimazole are rare. only a single isolate of candida guilliermondi has been reported to have primary resistance to clotrimazole. no single-step or multiple-step resistance to clotrimazole has developed during successive passages of candida albicans and trichophyton mentagrophytes . no appreciable change in sensitivity was detected after successive passage of isolates of c. albicans, c krusei , or c. pseudotropicalis in liquid or solid media containing clotrimazole. also, resistance could not be developed in chemically induced mutant strains of polyene-resistant isolates of c. albicans . slight, reversible resistance was noted in three isolates of c. albicans tested by one investigator. there is a single report that records the clinical emergence of c. albicans strain with considerable resistance to flucytosine and micronazole, and with cross-resistance to clotrimazole, the strain remained sensitive to nystatin and amphotericin b. in studies of the mechanism of action, the minimum fungicide concentration of clotrimazole caused leakage of intracellular phosphorus compounds into the ambient medium with concomitant breakdown of cellular nucleic acids and accelerated potassium efflux. both these events began rapidly and extensively after addition of the drug. clotrimazole appears to be well absorbed in humans following oral administration and is eliminated mainly as inactive metabolites. following topical and vaginal administration, however, clotrimazole appears to be minimally absorbed. six hours after the application of radioactive clotrimazole 1% cream and 1% solution onto intact and acutely inflamed skin, the concentration of clotrimazole varied from 100 mcg/cm 3 in the stratum corneum to 0.5 to 1 mcg/cm 3 in the stratum reticulare, and 0.1 mcg/cm 3 in the subcutis. no measurable amount of radioactivity (≤0.001 mcg/ml) was found in the serum within 48 hours after application under occlusive dressing of 0.5 ml of the solution or 0.8 g of the cream. only 0.5% or less of the applied radioactivity was excreted in the urine. following intravaginal administration of 100 mg 14 c-clotrimazole vaginal tablets to nine adult females, an average peak serum level, corresponding to only 0.03 μg equivalent/ml of clotrimazole, was reached one to two days after application. after intravaginal administration of 5 g of 1% 14 c-clotrimazole vaginal cream containing 50 mg active drug, to five subjects (one with candidal colpitis), serum levels corresponding to approximately 0.01 μg equivalents/ml were reached between 8 and 24 hours after application.